The Houston Center for Acquired Resistance Research (H-CARR)

总体总结 头颈部鳞状细胞癌(HNSCC)仍然是全球癌症死亡的主要原因 每年约500,000例。顺铂是治疗HNSCC的金标准全身用药。顺铂耐药，两者均为 固有的和后天的，已在临床前模型中描述，并在临床实践中经常遇到； 当它发生时，它是致命的。H-CARR的首要目标是发展一种强有力的生物学理解 HNSCC中顺铂耐药的关键驱动因素，并开发早期检测手段 并在它出现时克服它。我们之前的研究表明：1)细胞处理产生的顺铂 代谢应激是敏感性和/或耐药性的关键驱动因素，2)协调基因组(TP53突变) 转录(NRF-2激活)重编程对于组织顺铂的代谢反应是必不可少的 产生了压力。H-CARR结合了我们顺铂耐药的生物和代谢模型以及我们的 非侵入性成像肿瘤新陈代谢和使用循环检测生物移位的翻译能力 肿瘤细胞(CTCs)，以提供获得顺铂耐药的全面窗口，如 以下列出的项目，由组织成3个核心的强大的行政和分析基础设施提供支持。 项目1将使用最先进的代谢组学研究来确定关键的代谢依赖关系 顺铂耐药的HNSCC，识别有效代谢抑制的机会并提高我们的理解 顺铂耐药的获得与肿瘤免疫调节之间的相互作用 微环境。项目2将探索维持生物多样性所需的基因组和转录重组。 伴随耐药性发展的代谢变化，并询问NRF-2是如何依赖和 独立信号通过内在的细胞机制驱动耐药性和增强远处转移 以及肿瘤细胞和肾上腺素能神经元之间的旁分泌信号。项目3将测试新陈代谢是否 项目1中概述的重新编程可以通过非侵入性成像(超极化磁共振)进行检测 成像)，以及项目2中概述的由于克隆灭绝和扩张而产生的生物迁移是否可以 在接受顺铂治疗的患者中使用CTC分析进行检测。 H-CARR有可能通过识别获得的顺铂 在治疗过程中早期产生耐药性，并开发克服这种耐药性和相关表型的方法 作为增强的远处转移。成功完成拟议的实验将产生新的 顺铂在鼻咽癌及相关上皮性肿瘤中的临床应用 肺癌和食道癌，因此对癌症存活率有重大影响 全世界。

Overall SUMMARY Head and neck squamous cell carcinoma (HNSCC) remains a leading cause of cancer deaths worldwide with ~500,000 cases/year. Cisplatin is the gold standard systemic agent for HNSCC. Cisplatin resistance, both intrinsic and acquired, has been described in preclinical models and is frequently encountered in clinical practice; when it occurs it is deadly. The overarching goal of H-CARR is to develop a robust biological understanding of the key drivers of cisplatin resistance in HNSCC and develop the means of detecting it early in development and overcoming it once it arises. We previously showed that: 1) cellular processing of cisplatin generated metabolic stress is a critical driver of sensitivity and/or resistance and 2) coordinated genomic (TP53 mutation) and transcriptomic (Nrf-2 activation) reprogramming is essential to organizing the metabolic response to cisplatin generated stress. H-CARR brings together our biological and metabolic models of cisplatin resistance and our translational capabilities to image tumor metabolism non-invasively and detect biological shifts using circulating tumor cells (CTCs), to provide a comprehensive window into acquisition of cisplatin resistance as outlined in the Projects listed below, supported by a robust administrative and analytical infrastructure organized into 3 Cores. Project 1 will use state of the art metabolomic studies to identify the critical metabolic dependencies of cisplatin resistant HNSCC, identify opportunities for effective metabolic inhibition and improve our understanding of the cross-talk between the acquisition of cisplatin resistance and modulation of the tumor immune microenvironment. Project 2 will explore the genomic and transcriptomic reprogramming required to sustain the metabolic shifts which accompany development of resistance and interrogate how Nrf-2 dependent and independent signaling drives resistance and enhanced distant metastasis through intrinsic cellular mechanisms and paracrine signaling between tumor cells and adrenergic neurons. Project 3 will test whether the metabolic reprogramming outlined in Project 1 is detectable via non-invasive imaging (hyperpolarized magnetic resonance imaging) and whether the biological shifts outlined in Project 2 due to clonal extinction and expansion can be detected using CTC analysis in patients undergoing cisplatin-based treatment. H-CARR has the potential to realize the full clinical utility of cisplatin by identifying acquisition of resistance early during treatment and developing the means to overcome this and associated phenotypes such as enhanced distant metastasis. Successful completion of the proposed experiments will generate the new clinical standard for precision oncology approaches to clinical utilization of cisplatin in HNSCC and related upper- aerodigestive tract cancers of the lung and esophagus and therefore have a major impact on cancer survival worldwide.